A major goal of surgical and anesthetic care is to control the physical and emotional stresses that occur before, during, and after surgery. The human body uses systems of hormones and neurotransmitters to mediate stress responses; by identifying and characterizing these systems it may be possible safely and effectively to reduce the stress of surgery and improve clinical outcomes. We previously generated a line of mice that are lacking the gene for the neurokinin 1 (NK1) receptor, a protein that belongs to a family called the tachykinin receptors. Mice that lack the NK1 receptor display greatly decreased anxiety in a series of behavioral tests. We have recently developed evidence suggesting that two brain nuclei, the locus coeruleus and the dorsal raphe nucleus, may be the sites at which NK1 receptors mediate anxiety and stress responses. These nuclei provide projections throughout the brain and release the neurotransmitters norepinephrine and serotonin. Additional evidence suggests that another tachykinin receptor, the neurokinin 2 (NK2) receptor, may also regulate anxiety in these nuclei. This proposal aims to test the hypothesis that NK1 and NK2 receptors located in the locus coeruleus and dorsal raphe nucleus regulate anxiety and stress responses by influencing the activities of these nuclei. The neuropeptides that bind to NK1 and NK2 receptors, substance P and neurokinin A, are present in the locus coeruleus and dorsal raphe nucleus, but the locations of the neurons that produce these transmitters are not known. Another goal of this proposal is to define the circuitry that underlies the anxiolytic effects of tachykinins in these nuclei. This research will provide a better understanding of the neural and endocrine systems that contribute to the stress of surgery, which may in turn contribute to the development of therapeutic interventions that improve surgical and anesthetic outcomes.